Osteoarthritis (OA) is a debilitating and painful joint disease affecting an estimated 12% of the total United States population between 25-74 years of age. The incedence is even greater among obese individuals. The goal of this study is to understand how exercise training affects the pathogenesis of obesity-linked OA. We hypothesize that moderate exercise training mitigates and delays the onset of OA in diet-induced obese mice. To test this, we will study non-obese sedentary, obese sedentary, and obese exercise-trained mice. For each group we will determine: 1) voluntary cage activity levels, preferred speeds, and gait characteristics to better understand the factors affecting joint loading, 2) serum levels of pro-inflammatory cytokines (e.g. ILl, IL-17, and TNF-alpha), nitric oxide, and prostaglandins to understand the role of systemic inflammation in the pathogenesis of OA, and 3) compressive and tensile properties and histological grades of knee joint cartilage to quantify the parameters of cartilage degeneration that characterize OA. These studies will significantly improve our understanding of different mechanisms involved in the pathogenesis of OA and the efficacy of "biomechanical" therapies such as weight-loss and exercise in decreasing disease progression. [unreadable] [unreadable]